RAB6C is an independent prognostic factor of estrogen receptor‑positive/progesterone receptor‑negative breast cancer

Abstract

The majority of breast cancer tumors are estrogen receptor-positive (ER+) and can be treated with endocrine therapy. However, certain patients may exhibit a good prognosis without systemic treatment. The aim of the present study was to identify novel prognostic factors for patients with ER+ breast cancer tumors using gene copy data, and to investigate if these factors have prognostic value in subgroups categorized by progesterone receptor status (PR). Public data, including the whole genome gene copy data of 199 systemically untreated patients with ER+ tumors, were utilized in the present study. To assess prognostic value, patients were divided into two groups using the median gene copy number as a cut-off for the SNPs that were the most variable. One SNP was identified, which indicated that the Ras-related protein Rab-6C (RAB6C) gene may exhibit prognostic significance. Therefore, RAB6C protein expression was subsequently investigated in a second independent cohort, consisting of 469 systematically untreated patients (of which 310 were ER+) who received long term follow-up. In the public data set, a distant recurrence risk reduction of 55% was determined for copy numbers above the median value of RAB6C compared with numbers below [multivariable adjusted hazard ratio (HR), 0.45; 95% CI 0.28–0.72; P=0.001)]. It was also more pronounced in the ER+/PR− subgroup (HR, 0.15; 95% CI, 0.05–0.46; P=0.001). In the second cohort, patients of the ER+/PR− subgroup who exhibited high RAB6C expression had a reduced distant recurrence risk (HR, 0.17; 95% CI, 0.05–0.60; P=0.006). However, this was not identified among ER+/PR+ tumors (HR, 1.31; 95% CI, 0.69–2.48; P=0.41). The results of the present study indicated that RAB6C serves as an independent prognostic factor of distant recurrence risk in systemically untreated patients with an ER+/PR− tumor.

Low RAB6C expression is a predictor of tamoxifen benefit in estrogen receptor‑positive/progesterone receptor‑negative breast cancer

“…In cervical cancer, RAB6C promoter methylation analysis has been shown to have high sensitivity and specificity in distinguishing between malignant, premalignant and normal tissue, while in squamous cell carcinoma of the tongue, patients with low RAB6C expression levels had poorer survival times than those with high RAB6C expression (20,21). This is also in line with our study on the prognostic value of RAB6C in breast cancer (26). Furthermore, the long non-protein coding RAB6C antisense RNA 1 (RAB6C-AS1) is frequently overexpressed in gastric and breast cancer, and often deleted in prostate and pancreatic cancer and in brain tumors.…”

“…Patients with this tumor subtype are mostly treated with both endocrine therapy and chemotherapy, but there are probably subgroups of patients with these tumors who have high survival rates with more limited treatment. In a concurrent study, the results indicated that RAB6C may identify such patients (26). The present study further investigated the role of RAB6C in a retrospective study based on clinical data with patients randomized to be treated with endocrine therapy (tamoxifen) or included in the control group.…”

“…RAB6C also interacts with p53, which is frequently mutated in breast cancer (5-7). In a concurrent study, it was revealed Low RAB6C expression is a predictor of tamoxifen benefit in estrogen receptor-positive/progesterone receptor-negative breast cancer that systemically untreated patients with ER + /PRtumors and high RAB6C expression (RAB6C + ) had prolonged distant recurrence-free survival compared with that of patients with low RAB6C expression (RAB6C -) (26). The aim of the present study was to investigate if RAB6C has a treatment predictive value for tamoxifen.…”

Advanced Magnetic Resonance Imaging Modalities for Breast Cancer Diagnosis: An Overview of Recent Findings and Perspectives

“…It is noted that ADC maps contain weak anatomical details and can be studied alongside other MRI images [ 9 ]. Most breast tumors (75–80%) are positive for estrogen receptors, and ~75% of them are positive for progesterone receptors [ 10 ]. Variations in ADC values according to estrogen or progesterone receptor expression have been documented in different studies [ 11 , 12 , 13 ].…”

Stratification of Estrogen Receptor-Negative Breast Cancer Patients by Integrating the Somatic Mutations and Transcriptomic Data

“…Due to the lack of reliable biomarkers, it is impossible to identify ER − tumors with a good prognosis (Teschendorff et al, 2007 ; Zhang et al, 2016 ). Several studies have revealed that different chromosomal and gene expression patterns are present in patients with different estrogen receptor statuses (Zhang et al, 2009 ; Fohlin et al, 2020 ). Thus, an accurate grouping of ER − breast cancer into clinically relevant subtypes is of particular importance for therapeutic decision making.…”